Despite a wealth of pre-clinical animal studies over the past decade which had demonstrated the safety of gene therapy, the recent clinical experience of Cavazzana-Calvo, Fischer and co-workers with the treatment of children with SCID-X1 by gene therapy suggests that retroviral and lentiviral vector mediated gene therapies that employ existing technology may present a significant risk to patients. While there may be some difference in opinion with regard to the appropriateness of continuing clinical gene therapy studies that make use of existing technology, most would agree that the development of vectors with an improved safety profile would significantly accelerate the advancement of the clinical development of retroviral and lentiviral vector-based gene therapies. The proposed research program will focus on three technological areas of lentiviral vector development which we believe could have the most impact on safety profile of the vectors. These areas include the development of better and safer methods to produce lentiviral vectors suitable for clinical use, the development of more effective means to conditionally eliminate transduced cells and the development of methods to minimize the effects of lentiviral-mediated gene transfer on cellular gene expression. Overall, these studies should lead to the generation of valuable information, technology, and reagents that should be of broad interest to investigators working in the field of gene therapy, and should greatly accelerate the re-establishment of a strong clinical development effort in lentiviral vector-based gene therapy strategies.